VOLTAGE-GATED ION CHANNELS Voltage-Gated Sodium Channels

Antiepileptic drugs (AEDs) protect against seizures through interactions with a variety of cellular targets. By affecting the functional activity of these targets, AEDs suppress abnormal hypersynchronous activity in brain circuits, leading to protection against seizures. The actions on these targets can be categorized into four broad groups: (i) modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels; (ii) enhancement of GABA inhibition through effects on GABAA receptors, the GAT-1 GABA transporter, or GABA transaminase; (iii) direct modulation of synaptic release through effects on components of the release machinery, including SV2A and α2δ; and (iv) inhibition of synaptic excitation mediated by ionotropic glutamate receptors, including AMPA receptors (Table 43.1). The ultimate effects of these interactions are to modify the bursting properties of neurons and to reduce synchronization in localized neuronal ensembles. In addition, AEDs inhibit the spread of abnormal firing to distant sites. Some seizures, including typical generalized absence seizures, result from thalamocortical synchronization. AEDs effective in these seizure types interfere with the rhythm-generating mechanisms that underlie synchronized activity in the thalamocortical circuit. In this chapter, we consider each of the targets and discuss how AEDs affect the activity of these targets. Many AED targets are ion channels, most notably voltagegated sodium and potassium channels and GABAA receptors. It is interesting to note that certain idiopathic epilepsy syndromes are believed to be the result of mutations in these same ion channels (see Chapter 4).